The primary objective of this proposal is a quantitative definition of the relationship between the disposition and pharmacological effects of two narcotic analgesics, liter, Alpha-acetylmethadol (LAAM) and methadone. Studies will be conducted in three species man, rat and pregnant ewe. We will determine whether LAAM, a drug biotransformed to active metabolites, has any advantages over conventional narcotics in the management of paindue to cancer by conducting clinical analgesic assays and pharmacokinetic studies. We have developed a pharmacokinetic-pharmacodynamic (PK-PD) model for methadone analgesia in cancer and chronic pain patients. We will continue to test this model and then develop a PK-PD model for LAAM analgesia. These models will be used as guidelines for improved pain management by providing a better indication of the relationship between drug dose, plasma level and analgesia. We will develop a PK model for LAAM in maintenacne patients to assist in the individualization of dosing during induction. By use of the chronic pregnant ewe preparation we will define the pharmacokinetics of LAAM in mother and fetus following maternal and fetal administration of LAAM. We propose to use a novel approach (dosing to effect) to produce opiate tolerance and dependence to methadone and LAAM (and its metabolites) in the rat. We will measure the plasma drug concentrations associated with tolerance to distinguish functional from dispositional tolerance, determine the relationship between drug elimination kinetics and intensity and duration of withdrawal signs and evaluate drug interactions purported to modify tolerance and dependence. We will develop methods for the isolation and characterization of brain endorphins and determine the influence of opiate tolerance, dependence, and withdrawal on the processing of brain endorphins in the rat. By use of a newly developed method we will define the pharmacokinetics of heroin and its active metabolites in the rat. These studies will require HPLC and RIA methods.